Centella asiatica effects on neuroinflammatory responses in Drosophila models of acute inflammation and aging

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PROJECT SUMMARY Aging is characterized with dysregulated immune function contributing to the decline in biological resilience and increasing vulnerability to death. Aging individuals develop inflammaging, a state characterized by elevated levels of inflammatory cytokines, which contribute to the increase in chronic morbidity, frailty and lead to deterioration of neurological and functional resilience in the elderly. There are no approved interventions currently available to counteract the deleterious effects of inflammaging. Certain lifestyle modifications such as regular physical activity, calorie restriction and plant-based diet have been associated with decreased levels of chronic inflammation resulting in slowed biological aging. Numerous botanical dietary supplements are currently available on the market with claims to improve resilience to age-related deterioration in cognition, sleep or mood. However, the molecular mechanism of action for most of these formulations remains unknown. The BENFRA Botanical Dietary Supplements Research Center at OHSU has been involved in evaluating the potential of the Ayurvedic plant Centella asiatica (gotu kola) in alleviating age-related neurological changes. The research performed at the center has demonstrated that hot water gotu kola extract (CAW) has positive effects on antioxidant response, mitochondrial activity and synaptic health in both in vitro and in vivo preclinical mouse models. However, the previous research at the BENFRA center has not assessed the potential of standardized CAW extract to reduce brain specific inflammation in in vivo models of aging or acute neuroinflammation. In this application we propose to test the ability of CAW to ameliorate acute and age-related neuroinflammation in the genetically tractable organism Drosophila melanogaster. Similar to mammals, transcription of pro-inflammatory molecules in Drosophila is mediated by the evolutionarily conserved transcription factor NF-κB, whose activity also increases with age. Here, we will evaluate the effects of CAW on neuroinflammation in aging wild type Drosophila, in Drosophila with constitutively active innate immune system undergoing accelerated aging, and in a Drosophila model of Paraquat (PQ)-induced oxidative stress. In each model, using optimized CAW feeding regimens, we will assess survival, the levels of brain-specific inflammatory gene expression or oxidative stress markers. Moreover, we will test the effects of CAW on neurological outcomes by measuring mobility behavior and vacuolar neuropathology in brain tissue. This research will verify whether CAW lowers levels of inflammation in in vivo models of acute neuroinflammation and aging, and if it ameliorates associated neurological phenotypes. A demonstration that CAW can affect inflammaging will serve as the basis of including biomarkers of inflammation as important endpoints in future clinical trials of CAW.